N, n-diphenyl-n&#39;-aminoalkylene-urea derivatives



United States Patent N,N-DlPHENYL-N'-AMlNOALKYLENE-UREA DERIVATIVES John Krapcho, Perth Amboy, and William A. Lott, Maplewood, N. J., assignors to Olin Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Application August 4, 1954, Serial No. 447,927

Claims. (Cl. 260-553) This invention relates to new urea derivatives and more particularly to new l-(basically-substituted alkyl)- 3,3-diaryl ureas and acid-addition salts thereof.

The free base compounds of this invention may be represented by the following general formula:

wherein each of R and R represents an aromatic radical, preferably a 6 to 10 carbon-atom aromatic hydrocarbon radical or an inorganically (e. g. halo or amino)- substituted hydrocarbon radical or an alkoxy-substituted hydrocarbon radical (such as phenyl, tolyl, xylyl, naphthyl, chlorophenyl, bromophenyl, iodophenyl, dichlorophenyl, bromotolyl, iodoxylyl, chloronaphthyl, anisyl, ethoxyphenl, etc.); R is alkyl (preferably lower alkyl, such 'as methyl, ethyl, propyl, n-butyl, and n-hexyl) or alkenyl (preferably lower alkenyl, such as allyl, methallyl, Z-buteriyl, and Z-hexenyl); A is a lower alkylene radical separating the nitrogen atoms by at least two carbon atoms, and includes such radicals as ethylene, propylene, butylene, and 'hexylene, whether branched or straight chained; and NB is amino, monoalkylamino [preferably mono(lower alkyl)amino, such as methylamino, ethylamino, isopropylamino, and n-hexylamino], dialkylamino [preferably di(lower alkyl)amino, such as dimethylamino, diethylamino, ethylmethylamino, di(isopropyl)amino, dipropylamino, and dibutylamino], or an N-heterocyclic radical, such as piperidino, pyrrolidino, or morpholino.

Examples of suitable acid-addition salts of the free base compounds of this invention includes the mineral acid salts, such as the hydrohalides (e. g.'hyrdochloride, hydrobromide, and 'hydroiodide), the sulfate, and the phosphate; and the organic acid salts, such as the citrate, tartrate, oxalate, ascorbate, and succinate. (Pharmacologically-acceptable acids are of course employed where the salt form is prepared for therapeutic use.)

A particularly preferred class of the free base compounds of this invention may be represented by the following general formula NOOX 2 wherein X is' a halide (preferably chloride) with an alkylene di-amine of the formula R"NH-A--NB, to form a substituted urea of the formula NCN-A-NB-HX R1 RI! which may then be neutralized to the free base. Other acid-addition salts may be formed either by metathesis with a salt of the desired acid or by reaction of the free base with the desired acid.

The condensation of the carbamyl halide with the alkylene diamine is most advantageously achieved by heating the reactants in equimolecular proportions in an inert solvent, such as toluene or benzene, to a temperature of from C. to C. (preferably to reflux). The resulting hydrohalide salt may then be neutralized to the free base by treatment with an alkali, such as soditun hydroxide or potassium hydroxide.

The following examples are merely illustrative of suitable methods for'the practice of this invention, and are in no way to be considered limitative.

EXAMPLE 1 1- (Z-diethylaminoethyl) -3,3-diphenyl-1-methylurea A solution of 116 g. of diphenylcarbanyl chloride in 500 ml. of toluene is stirred, cooled, and treated dropwise with a solution of 70.0 g. of N,N-diethyl-N-methy1- ethylenediamine (J. Chem. Soc., 1935, 1425) in 200 ml. of toluene. The resulting mixture is refluxed for two hours, cooled and treated with a solution of 10 ml. of concentrated hydrochloric acid in 400 ml. of water. The aqueous layer is separated and the toluene phase extracted with 100 ml. ofwater. After combining the aqueous phases, it is basified with a cold solution of 32 g. of sodium hydroxide in 100 ml. of water. The liberated base is extracted with two 300 ml. portions of ether and dried over magnesium sulfate. After evaporation of the solvent, the residue is distilled; yield about 133 g. (about 82%); B. P. about l7918l C. (0.3 mm.).

EXAMPLE 2 I-(Z-diethylaminoethyl) -3,3-diphenyl-1-methylurea hydrochloride 133 g. of I-(Z-diethylaminoethyl)-3,3-diphenyllmethylurea (prepared by the method of Example 1) is dissolved in 200 ml. of ether and treated with one equivalent of hydrogen chloride in 104 ml. of absolute alcohol. After dilution of the resulting solution to 800 ml. with ether, a crystalline solid is separated, cooled, and filtered; yield about 142.5 g. (about 79%), M. P. about 114116 C. This material is recrystallized from 1.1 liters of ethyl acetate; yield about 136 g.; M. P. abou 114-116" C.

EXAMPLE 3 1- (2-diethylamin0ethyl) -3,3-diphenyl-I-e'thylurea A mixture of 33.2 g. of diphenylcarbamyl chloride in 200 ml. of benzene is treated with a solution of 21.0 g. of N,N,N'-.triethyl-ethylenediamine (J. Chem. Soc., 1935, 1425) in 100 ml. of benzene. The resulting mixture is refluxed for eight hours and the product then isolated as in Example 1; yield about 32.0 g.; B. P. about 181-193 C. (0.5 mm.).

EXAMPLE 4 1-(Z-diethylaminoethyl)-3,3-diphenyl-1-ethylurea hydrochloride 32.0 g. of 1-(2-diethylaminoethyl)-3,3-diphenyl-1- ethylurea (prepared by the method of Example 3) is EXAMl Iz'E "5 I-(Z-diethylaminoethyl) -1-isopropyl 3,3-diphenylurea A mixture of 33.2 g. of diphenylcarbamyl chloride and 23.7 g. of N,N-diethyl-N' disopropylethylenediarnine [ii'tihl Chifn. 6} 835 ("1951); Chem. -"Ab"stracts 47, 2695 (1953 :in 800311 ef benzene is refluxed for eight h'ours. Th'e pmduct is -isolated as in E-xainple 1;"yield' about 35.5 g.; M. P. about 174l76 Chi-0.2mm).

"EXAMPLE 6 =1 -.(-2'-diethylnmin'o'thyl.) d isopropyl-dj dipheny [urea '"hydmch lor iae 35. 5 g. or T-(Zdie'tliflaminothyl)-1 iSOpfpyl-3,3-dip'h'enylur'ea (preparediby the method of Example is treatedwithhn equivaIent-amount e't'hy'drogen chloride in accordance With "tlie'hi'e'thdd of Example 2. The hydrohloride salt isbbtaine'd in a 'yimof'about 38 Mi P.'"'about 1995 137 C. After recrystallization from 100 ml. of butanone,t'he prodnctwei'ghs about305 g.; M. P. about 161-462" C.

EX'AMPILE 7 1-(3 diethylaminopropyl)-3,'3*diphenyl-1methylurea Ainix'tureof 23.1. g. of diphnylcarbamyl chloride and 14.2 .1g. of N,N diethYI N' metliyL1;3 propanediamine ['Bull. so'c. Ch'im. ('5'), 6,501'('19'39);'Chem. Abstracts 33,5807 '19 39)] in 200 ml. ofbenzene is refiuxed'for two hours. Tltef'pr'odu'ct is isolated as in Example 1; yield 'about "2'8.0..'g.; B. P. "about 185 -189" 'C. (0.2-0.3 mm).

EXAMPLE '8 1-(3-diethy1aminopropyl) -3,3'-di-phenyl-I-methylurea hydrochloride 28.0 vg: of l-(3 diethylaminoprop'yl) 3,3 diphenyl-lmethylurea (prepared by' themethod' of Example "7) is treated-with an equivalentamount of hydrogen chloride in accordance with the method of Example 2. The hydrochloride salt obtained is. then recrystallized from a mixture of ethanol and'fdieth yl ether; M. P. about 140.5-141.5 C.

In a sim-ilar manner, by' substituting other alkylenediamines for the alkylenedia'mines inthe above 'o'ddnumbered examples, the corresponding "free rbases .are obtained. 'Thuswhenan equivalent 'amo'unt 'of N,N,N- trimethylethylenediamine or N,N-"dimethyl N"-'ethylethylenediamine' is substitu ted' for N,NN triethyl-ethylenediamine in Exaniple 3, 1-(2-dimethyl aminoethyl) 3,3-diphenyhl methylurea and l-(2-dimethylarninoethyl)3,3- diphenyl-l-ethyl urea are ob'taine d, respectivelyy and these may be converted to their hydrochloride salts by' the method of Example 2.

The method of the :above-odd-numbered examples is also useful in preparing 1-[w-(1-N-heterocyclic)-alkyl]- 33 diphenyl 1 flower alkyl') ureas by substituting w'-( 1- N-hetero'cyclic) alkyl-(lower 'alkyl) "aminesfo'r the diam'ines ofthe" example. Thus'N piperidirioethyl, methylai'nine,N pyrrolidinoethyl, 'ethylarnine, and N-rno'rpholiriopropyl, methy'larnine 1 yield 1- (2-piperidinoethyl)- 3 j3 dipl1'enyl l'rn'ethy'lurea, '1'- (2 pyrrolidi'noethyl )-3 3 diphenyl-l-ethylurea, and 1-(3 morpholinopropyl) 3,3- diphenyl-l-methylamine;zrespectively.

In a similar manner, by substituting other mineral and organic acids" for hydrogen chloride in" the above evennumbered examples, other-*acid addition salts may be formed. -'I'hus an:equivalent -amount of -hydrogen bromide or hydrogen iodide--form=the cor-responding hydrobromide and hydroiodide salts; and an equivalent amount of tartaric acid or citric acid yields the corresponding tartrate and citrate salts, respectively, etc.

EXAMPLE 9 1-(Z-dfethflaminoethyl) -1 ztllyl=3,3 diphenylarea (-a) 'Nallyl-N'-,N-die'thylethyienediaminew+A solution of 171 g. of -allylamine in 4'50 mlpofabsolutelaleohol is treated wtih 172g. sf-Q-diethylaminoethyl ehloride hy drochloride and then 120 g. of finely divided potassium carbonate. The resulting .mixture is refluxed for two hours and cooled. 400ml. fof Water is then added and the mixture is added :to-a:solution-of- 200 g. of sodium hydroxide in 400 ml. of Water. The product is extracted with ether and dried over magnesium sulfate. After evaporation of the solvent, the product is fractionated to y'ie'ld'about87.4 g. of-colorlessproduct 'B'. P. about 87 C.(25 mm.).

(b) 1- (2- tliethylaminoeihyl) 1- Zzllyl 3,3 -d iphenyl- 1.'rea.A mixture of25 gfiof diphenylcarbamyl chloride and 16.9 g. of the N-allyl-N,N-diethylethylenediamine produced in section 'a'in 450- ml.-'iof benzene is refluxed for two hours and the product-isolated as in Example 1; yield about 21.5 g.; E. P. about 182-193" C. (0.5 mm.).

EXAMPLE 10 "J -(2 diet/rylaminoethyl) -'1-allyZ-3,3-diphenylurea hy-droch loride 21.5 g. of '1-(2-diethylaminoethyl)-1-al1yl3,3diphenyl urea-(prepared'by the method of Example 9)r .is treated with an equivalent amount of hydrogen chloride in accordance -With the methodiof Example 2. The hydrochloride salt "formed is .ipurifiedby crystallization from ethyl acetate; yield. about 15 g.;' M. P. about 134.5- 136.5 C.

The compounds 1 of this invention 1 are useful as quickacting local anesthetics and also have antispasmodiciactivity Thus, l-Q2 dimethylaminoethyl)-3;3-diphenyl-lmethylurea hydrochloride (the compound of Example 2) is:mucl1 su'per-ior with :respect to rate ofl'onset than both 1 the corresponding 'demethylated derivative, 1-'( 2- diethylarminoethyl) 3g3diphenylurea hydrochloride, and Procainey as indicated by the :fo'llowing test*onrats. Each rat was injected intraperitoneally with 0.2 cc. of an: aqueous so'lution containing' the. indicated per cent L of l- Z-diethylaminoethyl) -3 ,3 diphenylurea hydrochloride, Procaine, and 1-(2 diethylaminoethyl)-3;3-diphenyl-1- methylureahydrochloride (indicated simply as methyl urea derivative" with the following results:

RAT SCIATIO NERVE BLOCK Composition gg ig 0.5% 1-(Z-diethylaminoethyl)-3,3-diphenylurea hydrochlo- 4 ii e .5 2% Procauie 4. 0 2% methyl urea. derivati 2. I 1% methyl urea derivative. 2. 2 0.5% methyl urea derivative 2. 6

5 We claim: 1. Compounds of the class consisting of: free bases having the general formula:

wherein R" is a radical selected from the class consisting of lower alkyl and lower alkenyl, A is a lower alkylene radical separating the nitrogen atoms by at least two carbon atoms, and NB is a radical selected from the class consisting of amino, mono-(lower alkyl) amino, di(lower alkyl) amino, piperidino, pyrollidino, and morpholino; and the pharmacologically-acceptable acid-addition salts thereof.

2. A 1-(dialkylaminoalky1)- 1- alkyl- 3,3- diphenylurea wherein each alkyl group is a lower alkyl radical.

3. A pharmacologically-acceptable acid-addition salt of a 1- (dialkylaminoalkyD- 1 alkyl 3,3 diphenylurea, wherein each alkyl group is a lower alkyl radical.

4. I-(Z-diethyIaminoethyD-S,B-diphenyl-l-methylurea.

5. 1-(2- diethylaminoethyD- 3,3- cliphenyl-lmethylurea hydrochloride.

6. 1-(2-diethylaminoethyD-3,3-diphenyl-l-isopropylurea hydrochloride.

7. A l-(dialkylaminoalkyD-l-(lower alkenyl)-3,3-diphenylurea wherein each alkyl group is a lower alkyl radical.

8. A tpharmacologically-acceptable acid-addition salt of 1-(dialkylaminoalkyl)-l-(lower alkenyl)-3,3-diphenylurea wherein each alkyl group is a lower alkyl radical.

9. 1-(2-diethy1aminoethyl)-l-allyl-3,3-diphenylurea.

10. 1- (2- diethylaminoethyD- 1- allyl- 3,3- diphenylurea hydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS 

1. COMPOUNDS OF THE CLASS CONSISTING OF: FREE BASES HAVING THE GENERAL FORMULA: 